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Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial

Andrew D. Zelenetz, Gilles Salles, Kylie D. Mason, Carla Casulo, Steven Le Gouill, Laurie H. Sehn, Herve Tilly, Guillaume Cartron, Martine E.D. Chamuleau, Andre Goy, Constantine S. Tam, Pieternella J. Lugtenburg, Adam M. Petrich, Arijit Sinha, Divya Samineni, Sylvia Herter, Ellen Ingalla, Edith Szafer-Glusman, Christian Klein, Deepak Sampath, Martin Kornacker, Mehrdad Mobasher and Franck Morschhauser

Key points

  • In this phase 1b study, venetoclax plus R-CHOP demonstrated manageable safety and promising activity in B-cell NHL.

  • Recommended dose of venetoclax was established as 800 mg (Days 4-10, Cycle 1; Days 1-10, Cycles 2-8) in combination with standard R-CHOP.

Abstract

Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (FL; 43%) or diffuse large B-cell lymphoma (DLBCL; 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/day), after which dosing was changed from daily to 10 days/cycle and escalated to 800 mg. A further reduction to 5 days/cycle occurred at the 800 mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2+ and MYC+) DLBCL patients (87.5%; n=7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4-10 of cycle 1 and days 1-10 of cycles 2-8; higher doses were not explored and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study. ClinicalTrials.gov identifier: NCT02055820.

  • Submitted November 8, 2018.
  • Accepted February 25, 2019.